Research Article ISSN 2639-9342 Gynecology & Reproductive Health

Premature Ovarian Insufficiency: Under-Diagnosis and Diagnostic Opportunities Professor Lukman Yusuf MD, PhD1* and Associate professor Shiferaw Negash MD2

*Correspondence: 1Department of Obstetrics and Gynecology, College of Health Professor Lukman Yusuf, Department of Obstetrics and Sciences, School of Medicine, Addis Ababa University. Gynecology, College of Health Sciences, School of Medicine, Addis Ababa University. 2Addis Ababa, Ethiopia. Received: 18 July 2020; Accepted: 07 August 2020

Citation: Yusuf L, Negash S. Premature Ovarian Insufficiency: Under-Diagnosis and Diagnostic Opportunities. Gynecol Reprod Health. 2020; 4(4): 1-9.

ABSTRACT Background: Premature ovarian insufficiency (POI) is basically cessation of menses, irregular menstruation or reduced fertility before the age of 40 years. It occurs in about 1% of the women population although younger women are not immune. The ultimate pathophysiology centers on the depletion of follicles and/or loss of endocrine function of the ovaries. Most commonly, it is idiopathic but possibly could be secondary to iatrogenic factors or a multitude of clinical conditions. Unlike natural menopause or acute ovarian failure, pregnancy is possible.

Objective: The study will provide valuable information in the prevalence, clinical presentations and counseling of patients regarding the management options for the affected individuals.

Setting: A clinical setting in the Ob-Gyn specialty clinic.

Methods: All prospective, consecutive patients attending Ob-Gyn clinical services with complaints of irregular menstrual bleeding including amenorrhea and those visiting us for preconception fertility counseling and infertility. The study was conducted during the period extending from January 1, 2020 to June 30, 2020. Variables considered included socio-demographic characteristics like age, religion, ethnicity, residence, socioeconomic status (educational achievement, family monthly income) along with their obstetric performance and menstrual history. Transvaginal ultrasonographic findings and laboratory tests, especially and more importantly of the fertility panel and Anti-Müllerian hormone (AMH) were determined and documented. The variables extrapolated ensured accuracy, avoided redundancy and maintained confidentiality. The data was entered, cleaned and analyzed using Epi-Info statistics software program. Descriptive statistics like mean and median for quantitative and proportion/percentage for qualitative variables were used, respectively. Level of significance was set at P-value <0.05.

Inclusion and exclusion criteria were set so that only patients with established scenario of hypergonadotrophic hypogonadism and diminished ovarian reserve vis-à-vis the AMH were availed.

Results: Out of a total of 5348 gynecological patients, 130 were diagnosed to have premature ovarian insufficiency giving a prevalence rate of 2.4%. Among the subjects with POI, three (2.3%) achieved spontaneous pregnancy with folic acid and vitamin D with calcium prenatal supplementation, despite guarded prognostication and suggestion for donor egg or embryo transfer and intent to liaise them to where it is routinely practiced. The mean age was 34.8+ SD4.8 with the range being between 21-39 years. Their clinical presentations in the order of frequency were predominantly secondary and primary infertility and oligo-amenorrhea of up to three months followed by sign and symptom complexes of postmenopausal syndrome. The diagnosis was ascertained by ovarian reserve testing with ultrasound, blood tests that encompassed AMH, FSH, LH, estrogen, progesterone, thyroid function tests, serum prolactin and serum vitamin D and calcium levels.

Conclusion: The study provides us with mounting evidence supported by the laboratory results that premature ovarian insufficiency is not a rare phenomenon and cites similarities reinforcing the fact that it is relatively more common than we anticipate. The available diagnostic means in such a low resource setting comfortably enables the capturing of the patients timely and channeling them for proper and comprehensive management options as deemed necessary.

Gynecol Reprod Health, 2020 Volume 4 | Issue 4 | 1 of 9 Keywords Hashimoto’s disease, Grave’s disease, hypoparathyroidism, Premature Ovarian Insufficiency (POI), Premature Ovarian Failure pernicious anemia, auto-immune hemolytic anemia, ITPP, Type (POF), AMH (Anti-Müllerian hormone), Ethiopia. I Diabetes Mellitus (DM), vitiligo, idiopathic Addison’s disease and myasthenia gravis, karyotyping vis-à-vis gonadal dysgenesis Abbreviations Turner’s and Fragile X syndrome as well as pelvic irradiation, AMH: Anti Müllerian hormone; ART: Assisted Reproductive excessive surgical removal or drilling of ovarian tissue (acute Techniques; FSH: Follicle Stimulating Hormone; HBsAg: ovarian failure), chemotherapy and immunosuppression. Other Hepatitis B Surface Antigen; HCV Antibody: Hepatitis C Virus incriminated factors include viral infections, tuberculosis, Antibody; HIV: Human Immuno-deficiency Virus; HRT: Hormone chemicals, toxins and cigarette smoking. A series of investigations Replacement Therapy; ITPP: Idiopathic Thrombocytopenic commensurate with the management plan need to relate or Purpura; IUI:Intra Uterine Insemination; IUTPI/DIPI/FSP: correspond with the causal factors [7-9]. Intrauterine Tuboperitoneal Insemination; Direct Intraperitoneal Insemination; Fallopian tube Specialist Perfusion Program; IVF- The treatment options comprise of high doses of ethinylestradiol ET: In-Vitro Fertilization and Embryo Transfer; LH: Luteinizing (EE) for breast development, pubertal growth and sexual maturity, hormone; PCOS: Polycystic Ovarian Syndrome; POF: Premature mental, physical and social support in the very young. Prevention ovarian failure; POI: Premature Ovarian Insufficiency; RPR: Rapid of osteoporosis and cardiovascular diseases and promotion of Plasma Reagin; TPHA: Treponema Pallidum Haemagglutination sound sexual health and provision of treatment options like donor Antigen; TFT: Thyroid Function Test; VDRL: Venereal Disease egg with IVF and adoption are in the order of management plan. Research Laboratory. The administration of DHEA (Diethylepiandrosterone) increases a spontaneously conceived pregnancies, decrease spontaneous Introduction miscarriage rates and improve IVF success rates in women with Premature ovarian insufficiency (POI) entails a conundrum POI. When considering options like IVF, IUI, IUTPI/DIPI/FSP or of semantic issues for an entity expressing overlapping natural conception, one ought to exercise caution for fear of aortic pathophysiologic changes with similar clinical signs and symptoms rupture in Turner’s syndrome patients during pregnancy. Advanced but implying differences in the physical, mental and social well management choices include ovarian tissue cryopreservation in being of the individual. It was first described as POI by Fuller prepubertal individuals at risk, fragmenting of ovaries with Akt Albright in 1942 [1,2]. The connotation of premature menopause/ stimulators and autografting and hormonal therapy, and treatment premature precoce (praecox) if defined with low estrogen levels and with estradiol skin patch or vaginal ring by-passing the first pass higher values of FSH in the menopausal range and with the ultimate effect on the liver and medroxyprogesterone acetate per day for cessation of menses for over a year is quite troubling to the client and days one through 12 of each calendar month [10]. family as opposed to premature ovarian insufficiency which may be expressed with intermittent resumption of function, occasional More important in the management is counseling of patients and menstrual periods and pregnancy achievements. Primary ovarian families regarding their future fertility, risk of comorbidities, and failure with no menarche is invariably and strongly associated potential for genetic inheritance. Psychological counseling for with gonadal dysgenesis or X-chromosome anomalies. Premature the impaired self esteem, emotional distress and HRT for sexual ovarian insufficiency (POI) and decreased ovarian reserve tend to health and prevention of osteoporosis and cardiovascular diseases be reconciliatory than premature ovarian failure (WHO III) which ought to be part of the order of treatment. Furthermore, annual denotes an irreversible hypergonadotrophic/hypogonadism state general checkup for comorbidities and genetic inheritance should or the aforementioned terminologies that do not imply permanent be part of the future plan [11,12]. ovarian failure bearing in mind that pregnancies can spontaneously occur in 5 to 10% of such a population [2-4]. The prevalence of premature ovarian insufficiency is far more beyond case presentations [13] and deserves comprehensive Hence, premature ovarian insufficiency (POI) is the loss or analysis and documentation. Furthermore, an Ethiopian study depletion of function (diminished ovarian reserve), dysfunction on prevalence and severity of symptoms on peri, menopause and of the ovaries or loss of eggs resulting in variable estrogen post menopause was conducted on age range of 30-49 which is and FSH levels with marked fluctuation of menstrual patterns also inclusive of the very young without delineation from POI characteristically before the age of 40 years but surely after [14]. Therefore, the study highlights the existence of limited data, menarche. It tends to occur in about 1% of the women population appreciates the diversity of clinical presentations and addresses the as opposed to the natural physiological menopause that occurs at individual personal desires regarding fertility. 51 + 5years of age. The hallmark of the diagnosis in POI is based on menstrual irregularity for at least in three consecutive months with Materials and Methods variable fertility patterns and deranged fertility hormonal panel [5,6]. All consecutive patients visiting the gynecology outpatient services at YHC in Addis Ababa, Ethiopia with complaints of infertility The causes are diverse and could be spontaneous or induced. and oligo-amenorrhoea were recruited for the purpose of this study Though not exhaustive, may include autoimmune diseases like during the period extending from January 1 through June 30, 2020.

Gynecol Reprod Health, 2020 Volume 4 | Issue 4 | 2 of 9 The time interval of six months was set under the assumption that quantitative variables and proportions/percentages for qualitative enough cases would be collected by then. A total of 5348 patients variables were made. The statistics software employed was Epi- were seen and those with the aforementioned symptom complexes info Version 3.5.1. making up for a rate of premature ovarian insufficiency (POI) of 2.4%. The cut-off age for POI was less than 40 years of age. Results Amazingly, three patients spontaneously achieved pregnancy with Out of 5348 clients, 130 were diagnosed to have premature ovarian folic acid, vitamin D and calcium supplements. insufficiency and the computed prevalence rate was put at 2.4%. Among the studied subjects with spontaneous-onset POI, 3(2.3%) A complete set of information pertaining to premature ovarian achieved spontaneous pregnancy and no attempt for ovulation insufficiency (POI) in general as an instrument to diagnose and induction was made as their AMH levels were less than 0.5ng/ plan the clinical management was obtained. Thus, an amalgam of ml which was labeled as a level “predictive of poor response”. A the present and past medical history including family history with significant proportion of the clients were referred by physicians, infertility, obstetric history and general physical examinations and some being self referrals mainly for infertility workup and were routinely performed and documented. counseling.

Relevant laboratory investigations that encompass karyotyping The scope of the age range of the studied population extends from whenever indicated, blood tests for fertility panel, thyroid function 21-39 with a mean age of 34.8 ± 4.8 years; and noteworthy is assessment, prolactin level, quantitative βHCG or urine pregnancy that about 112 (86%) of them fall within the range of 30-39 years tests and transvaginal ultrasound to study for the shriveling, (Table 1). As presented in Table 1, most of them were married enlargement or polycystic nature of the ovaries were part of the 113 (86.9%) with relatively low parity rate as accounted for by 84 detailed investigations. (64.1%) of nullipara and a cumulative percentage of 102 (78.4%) when primiparas are included. Majority of the patients were of An emphasis was put on the serum Anti-Müllerian hormone, a Christian faith followed by Muslims mainly coming from Addis biomarker of ovarian reserve, follicle development and to assess Ababa and Somaliland, respectively and most are housewives with for menopausal status and premature ovarian failure as well as for diverse distribution of their educational status, occupation, family the evaluation of the functional intactness and responsiveness of income; and ethnic wise they were mainly Amharas and Somalis the ovaries for infertility and success of IVF-ET. In the female, it (Table 1). is also an auxiliary aid in the diagnosis, recruitment and analysis of POI patients and exclusion of ambiguous genitalia/intersex, PCOS Of the patients, 41 (31.5%) and 3 (2.3%) have had history of and granulosa cell tumors of the ovaries. Pregnancy was ruled in miscarriage and ectopic pregnancy, respectively. All of them or ruled out in all of the studied population presenting with history were sero-negative for HIV, HBsAg and HCV Antibody and of delayed or absence of menses. furthermore their VDRL, TPHA and RPR tests were not yielding. Inclusion criteria included all non-pregnant clients who consented, Their thyroid function tests and serum prolactin levels were within were less than 40 years of age, have had their menarche and those normal ranges. who were never subjected for non-invasive or invasive operations along the hypothalamo-pituitary-ovarian-uterine and vaginal Their mean age at menarche was 13.7 ± 1.9 years with a median of axis that resulted in a detrimental impact on the obstetrical and 14 years and a range of 10-19 years; and its relevance is very much gynecological performance of the individual. dependent on the dictum that early menarche and early menopause, late menarche and late menopause could be in the interplay (Table The exclusion criteria encompassed all clients with completed 2) although no statistical significance was established as evidenced age of 40 or more years; and patients with polycystic ovaries, by Correlation Coefficient: r^2=0.00, P-value=0.427. hyperprolacinemia, gonadal dysgenesis or those who had underwent bilateral salpingo-oophorectomy with or without The primary complaints upon presentation in the order of hysterectomy and those subjected for chemotherapy, radiotherapy frequency, as shown in Table 3, were secondary and primary and those who experienced primary amenorrhea and never infertility and oligo-amenorrhea of up to three months followed by registered or experienced menarche. Under scrutiny were also sign and symptom complexes of postmenopausal syndrome. These those who were found to have hypogonadotrphic/hypogonadism clinical manifestations among POI patients are not as pronounced (WHO I) as hypothalamic pituitary failure and normogonadotropic/ as in postmenopausal women though they hardly accept the reality anovulatory (WHO II) designated as hypothothalamic pituitary that they are basically in similar clinical states. dysfunction. Those with mental retardation, teens of less than 18 and those who were not able to give a verbal consent for whatever The pertinent laboratory parametric values are presented in Table reason were also excluded from the study. 4. The laboratory results when properly dissected and plotted markedly enrich their clinical significance. The FSH, LH, estrogen The data collected for the study period was entered, cleaned, and progesterone levels are impressively commensurate with the and analysis for mean with standard deviation or median for postmenopausal ranges and their relationships are well established

Gynecol Reprod Health, 2020 Volume 4 | Issue 4 | 3 of 9 Characteristics Number Percent 20-24 7 5.4 25-29 11 8.5 Age (years) 30-34 27 20.7 35-39 85 65.4 Single/Cohabitating 17 13.1 Marital status Married 113 86.9 Nullipara 84 64.6 Primipara 18 13.8 Parity Secundipara & three 16 12.3 Para 4 or more 12 9.2 Orthodox Christian 69 53.1 Religion Muslim 56 43.1 Protestant 5 3.8 Amhara 56 43.1 Oromo 16 12.3 Ethnicity Guraghe 13 10.0 Somali 42 32.3 Tigre 3 2.3 Addis Ababa 72 55.4

Address Somaliland 42 32.3 Regions 14 10.8 Eritrea 2 1.5 Housewife 62 47.7 Self employed 30 23.1 Occupation Government employee 26 20.0 Private institutions 8 6.1 NGO 4 3.1 Illiterate 37 28.5

Educational status Primary 27 20.8 High school 30 23.1 College and above 36 27.7 Less than 2,000* 1 0.8

Family income 2,001-5,000 72 55.4 5,001-10,000 29 22.3 More than 10,000 28 21.5 * Ethiopian currency; 1USD = 38 Ethiopian Birr at the time of analysis

Table 1: Socio-demographic Features, January-June, 20.

Age of Menarche Frequency Percent Cum Percent 10 4 3.1% 3.1% 11 16 12.3% 15.4% 12 22 16.9% 32.3% 13 14 10.8% 43.1% 14 19 14.6% 57.7% 15 32 24.6% 82.3% 16 16 12.3% 94.6% 17 6 4.6% 99.2% 19 1 0.8% 100.0% Total 130 100.0% 100.0% Mean 13.7 ± 1.9, Median 14 years, Age range 10-19 years Table 2: Age of menarche.

Gynecol Reprod Health, 2020 Volume 4 | Issue 4 | 4 of 9 (Figures 1-3). As shown in Figure 1, as age increases, the level Discussion of AMH tends to decrease (Correlation Coefficient: r˄=2, P-value The ovaries are paired organs of 3-5 x 1.5-3 x 0.6-1.5 cm in size <0.05). AMH levels define an inverse, negative, relationship but and weighing 5-8gm (15). They produce 6-7 million follicles strong correlation with FSH values with Correlation Coefficient: at about 20 weeks of gestation of the female fetus in utero; of r˄=2, P-value <0.05 (Figure 2). AMH and estradiol levels, which 1-2 million are around at birth, 300,000-400,000 during as depicted in Figure 3, show a weak but positive correlation the reproductive life span and 300-400 ovulate during a woman’s (Correlation Coefficient:r ˄=0.03, P-value <0.05). reproductive age at a rate of 20-30 follicles per cycle just to release one mature Graaffian follicle. Most of them undergo atresia and The salient points from the clinical interpretations of AMH (Table this is a continuous process that tends to be unaffected by the age 5) provide clear information from severely diminished to ovarian of onset of menarche and POI. Thus the end result is scarification reserves that would be considered of limited response if they were from the follicles that constantly undergo the process of atresia/ to be challenged with ovulation inducing drugs and stimulated as apoptosis thereby contributing towards the depletion of the part of evaluation for assisted reproductive techniques/technology. primordial follicles and undermining the continuity of its hormonal and biological functionality in reproduction [16-18]. The relative vitamin D deficiency which is rampant among the population is also reflected in the scatter plot and is substantiated Climacterium is the time interval depicting a transitional phase by the correlation in the Figure 4. The close association of vitamin from the end of the reproductive periods starting at 40 or more D and total serum calcium level demonstrates strong and positive years of age and entering senility at 60 years of age which is correlation (Correlation Coefficient: r˄=0.06, P-value <0.05) characterized by the hallmark of involution and atrophy of though may not establish a cause and effect relationship but yet the reproductive systems secondary to a hypergonadotropic can impact individual fertility potential. The prolactin and hypogonadism state. In contrast, premature ovarian insufficiency serum testosterone levels did not weigh in as clinically of great with raised gonadotrophins and hypogonadism condition occurs relevance. after menarche but before the age of 40 years deviating from an

Variables Number Percent Primary infertility 43 33.1 Secondary infertility 52 40.0 Amenorrhea of > 3 months 32 24.6 Menopausal signs & symptoms* 3 2.3 Table 3: Presenting complaints. *Hotflushes, sweating, vertigo, tingling sensations/hands, chest pain/prickly sensation, tachycardia, hypertension, headache, tinnitus, psyche {hypomania/ depression/ melancholic/ hysterical}, irritability, decreased libido, amnestic forgetfulness, decreased performance, sleeplessness, loss of breast and adipose tissues, osteoporosis, atherosclerosis, diabetes mellitus.

Variables Mean with SD Median Range Anti Müllerian hormone (AMH) in ng/ml 0.153 ± 0.215 0.0375 0.010-0.850 Follicle Stimulating hormone in mIU/ml 48.077 ± 17.765 44.350 25-99 Luteinizing hormone in mIU/ml 39.754 ± 12.188 40.555 40.555-40.555 Estradiol in pg/ml 45.446 ± 15.463 45.000 12,000-87.000 Progesterone in ng/ml 0.717 ± 1.421 0.400 0.050-10.200 Testosterone in ng/ml 0.537 ± 0.508 0.360 0.040-3.210 Prolactin in ng/ml 13.431± 4.997 12.500 5.000-27.000 Vitamin D in ng/ml 15.379 ± 4.997 15.010 0.900-27.980 Serum calcium in ng/ml 9,054 ± 0.330 9.000 8.010-10.000 Table 4: Laboratory results.

Result AMH level in ng/ml* Remarks Number Percent <0.5 116 89.2 Predictive of poor response 0.5 - <1.0 24 10.8 Suggestive of limited reserve 1.0 - <3.5 - - Predictive of optimal response >3.5 - - Predictive of hyperstimulation/PCOS Table 5: Clinical interpretation of AMH. AMH (adopted from Star Metropolis Clinical Laboratories, 802-803 8th Floor Al Musalla Towers, Bur dabi, Dubai, UAE).

Gynecol Reprod Health, 2020 Volume 4 | Issue 4 | 5 of 9 Figure 1: Scatter plot of Age vs. AMH levels. Correlation Coefficient: r^2= 0.00, P-Value <0.05.

Figure 2: Scatter plot of relationship of AMH and FSH levels. Correlation Coefficient : r^2= 0.02, P-Value <0.05

Figure 3: Scatter plot of relationship between estrogen and AMH levels Correlation Coefficient : r^2= 0.03, P-Value <0.05

Gynecol Reprod Health, 2020 Volume 4 | Issue 4 | 6 of 9 Figure 4: Scatter plot of relationship of vitamin D and serum calcium. Correlation Coefficient : r^2= 0.06, P-Value <0.05.

Ethiopian study on menopause between the ages 30-49 as our incidence in those less than 40 years of age as corroborated in the current undertaking considers the POI as an entity distinct from present study is not a rare condition and its incidence is estimated menopause and its subgroupings [14]. to be as great as 1 in 100 by the age of 40, and 1 in 10,000 by the age of 20 years, 1 in 1000 by 30 years of age. It is to be highlighted A total of 130 patients with a fertility panel suggestive of that in women with primary amenorrhea the prevalence rate is 10- hypergonadotrophic hypoganadism (WHO III) labeled as 28%; and in those with secondary and/or iatrogenic amenorrhea, premature ovarian insufficiency are represented in current premature ovarian failure occurs in 4-18% [6,19,22-24]. study. The hypogonadotrophic hypogoanadism (WHO I) i.e. hypothalamic pituitary failure and normgonadotrophic It is a common understanding that fertility declines past the age anovulatory (WHO II) that implies hypothalamic pituitary of 35 which is regarded as an advanced maternal age. Our study dysfunction were excluded from the study in order to retain a is indicative of the fact that there is aggregation of diminished homogenous population possibly with diminished or ovarian ovarian reserve towards the age of 40 years which can be verified reserve. It is often stated that it is idiopiathic in 90% of the cases by employing ovarian reserve tests with AMH and complementary but other attributed or incriminated factors are autoimmune transvaginal ultrasonographic evaluation for shriveling ovaries but diseases and chromosomal abnormalities in addition to treatment holds true that the correlation exists only past > 35 years of age sequelae like pelvic irradiation, excessive removal and/or drilling [4,15,23-25]. of ovarian tissue, chemotherapy, and immunosuppression as well as toxins, cigarette smoking and infectious causes [8,9,19]. It is The quantitative antral follicle counts (AFC) and the qualitative thus a universal phenomenon demanding attention especially in properties of the follicles because of ovarian senescence with the presence of improved diagnostic capabilities and availing a marked increase in chromosomal/genetic abnormalities of the variety of management options. follicles poses a challenge in deciding for ART. AMH starts declining years prior to rise in FSH and is a sensitive biomarker of Furthermore, in establishing the diagnosis as in other studies, ovarian primordial follicular reserve. It has age specific ranges and AMH, fertility panel, prolactin level, TSH, vitamin D and other also broader clinical interpretations for ovarian reserve but with parameters were utilized as instruments to define the diagnosis the former, the values are at times out of range and falling in the [19-21]. Through these means, it was possible to distinguish the much advanced age groups. Its low values with increase in age and four clinical states of occult POI, biochemical POI, overt POI, and its preponderance past the age ≥ 35 years provides an opportunity the irreversible permanent cessation of menses with climacteric in establishing the diagnosis of POI as vividly demonstrated in this syndromes of premature ovarian failure in the extreme with study. The diagnosis was mirrored by the performed diagnostic follicular depletion and hypergonadotrophic hypogonadism. The opportunities though admissibly no blanket approach was assumed overall calculated prevalence rate was 2.4% and is quite similar and patients were not tailored/subjected to have their inhibin B with the often quoted rate of 1-2% as in the Swedish study. In levels, in conjunction with AMH, determined. The peptide inhibin conclusion, it is an acceptable and established phenomenon that the B blood levels decline in advanced maternal age especially in

Gynecol Reprod Health, 2020 Volume 4 | Issue 4 | 7 of 9 the presence of fewer follicles and diminished secretion by the phytoestrogens or combined oral contraceptive pills as other granulosa cells and it would have been strongly complementary combined postmenopausal preparations are not available; calcium with AMH, had it been possible and available in the country. and vitamin D supplements, regular physical activity and a healthy body weight and treatment for any associated conditions and Delayed diagnosis based on the quest for an answer to their assuring them of a glimmer of hope that there exist a possibility immediate clinical presentations were likely due to oligo- of intermittent resumption of ovarian functions and a 5-10% rate amenorrhoea, primary or secondary infertility; and sign and of spontaneous pregnancy [29-34]. In desperate situations in terms symptom complexes of menopause which are not as pronounced of time and ultimate option in delayed infertility cases, the clients as in natural or iatrogenic menopause although they may overlap are liaised to infertility clinics both at home and abroad with [8,9,12,15,26]. They fared better with vasomotor, neurovegetative available assisted reproductive technology services depending and psychological impacts that may include anxiety, depression, on their choice and financial capability. In general, it demands a insomnia, irritability, and worry about aging, identity crisis and multidisciplinary approach involving gynecologists, psychologists loss of prestige. However, once the diagnosis of premature ovarian and counselors, reproductive subspecialists, endocrinologists and insufficiency is established and it is only then after the implications internists with broader scale of diagnostic facilities and treatment of untimely ageing, inability to have or procure more children, social withdrawal in addition to hopelessness and depression/ of co-morbidities. including melancholy, marital disharmony and being disavowed, sexual incompatibility or disharmony tend to be an immediate The study demonstrated that premature ovarian insufficiency is discussion points [27]. not a rare phenomenon. An elevated gonadotrophic hormones and hypogonadism with resultant clinical manifestations of involuntary In a relatively high parity population as in our country and Somalia infertility and abnormal uterine bleeding with diminished ovarian in general, such a low parity level among the studied population reserve as verified with AMH determinations establish the basis of is analogous with subfertility designated population. Intermittent the diagnosis. POI is divergent from the usual complex heralding and unpredictable ovarian functions can result in spontaneous manifestations of physiologic, anatomical and pathological pregnancies and hence the fertility panel patterns unpredictably changes with vasomotor, genitourinary and psychological clinical highly variable in time relating to the poor ovarian reserve both signs and symptoms. in quality and quantity with low numbers of ovarian follicles or impaired folliculogenesis [15,19]. This is attested by the three The limitations include a clinical setup with clustering of referred individuals who spontaneously achieved pregnancies and are patient population for fertility workup, limited to the specified nearing term at about the time of this analysis and reporting. time frame, expensive laboratory investigations and the financial burden incurred by the patients and difficulty in conducting a The association of vitamin D and infertility is well established comparative study. A multi-centered national comparative study and hence vitamin D supplementation along with calcium in supported with adequate funding should be carried out on this very order to fulfill their extra needs in the prenatal and natal periods important topic. is highly recommended. 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